Cardiovascular Disease, Aging, and Clonal Hematopoiesis

Abstract

Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoietic cells and cardiovascular disease. Here, we provide an up-to-date review of clonal hematopoiesis and its association with aging and cardiovascular disease. We also give a detailed report of the experimental studies that have been instrumental in understanding the relationship between clonal hematopoiesis and cardiovascular disease and have shed light on the mechanisms by which hematopoietic somatic mutations contribute to disease pathology.

Keywords: ARCH; CHIP; DNMT3A; IL-1β; TET2; age-related clonal hematopoiesis; clonal hematopoiesis of indeterminate potential; somatic mutations.

Figure 1

Summary of reported prevalence of clonal hematopoiesis. The bar graphs represent the total number of individuals with clonal hematopoiesis associated with (magenta) and without (gray) known driver gene mutations reported in three independent studies (13, 15, 31). The donuts summarize the frequencies of somatic mutations in candidate driver genes; the numbers within the donuts indicate the total number of driver gene mutations detected. Abbreviations: CH-CD, clonal hematopoiesis with candidate driver mutations; CH-UD, clonal hematopoiesis with unknown driver mutations; SNV, single nucleotide variant; VAF, variant allele frequency.

Figure 2

Central overview of age-related clonal hematopoiesis and how it drives cardiovascular disease progression. During the aging process, healthy hematopoietic stem cells (HSCs) may acquire a mutation in a driver gene. This mutation provides the mutant HSC with a competitive advantage, allowing for its expansion at a disproportionate rate compared with other HSCs within the bone marrow niche (clonal expansion). As a result, the HSC-derived mutation propagates through the hematopoietic system and into its immediate leukocyte progeny, giving rise to a genetically distinct population of mature white blood cells. During cardiovascular disease, inflammatory cells migrate to the injury site and are involved in promoting disease pathogenesis through a variety of mechanisms. In the setting of clonal hematopoiesis, HSC-derived mutations may result in changes to the inflammatory profile of the leukocyte progeny(i.e., elevated cytokine production). As a result, this altered inflammatory profile of leukocytes can exacerbate cardiovascular injury processes, driving disease progression.

Figure 3

TET2-mediated clonal hematopoiesis accelerates cardiovascular disease through aberrant IL-1β signaling. Somatic mutations in TET2 within hematopoietic stem and progenitor cells lead to their clonal expansion, giving rise to myeloid cells that promote cardiovascular disease via aberrant activation of the NLRP3/IL-1β pathway (–53). Blockade of the NLRP3 inflammasome complex has been shown to reduce disease pathology associated with Tet2 clonal hematopoiesis in mouse models of atherosclerosis and heart failure (51, 53). Moreover, a subanalysis of the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial indicated that individuals with somatic mutations in TET2 responded more favorably to the IL-1β neutralizing antibody canakinumab than did individuals without TET2 mutations (–68). Abbreviations: IL, interleukin; MACE, major adverse cardiovascular event.